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Nucleoside Analogues: Future of Chemotherapeutic Agents

P. Merino, T. Tejero, F.L. Merchan, S. Franco, P. Romero, J.A. Matés, V. Mannucci

Bioorganic Chemistry Research Group

In the therapy of infections caused by viruses and also in the treatment of certain neoplastic diseases, nucleoside analogues have emerged as major chemotherapeutic agents. Since the discovery that nucleoside analogues can effectively protect cells from the lethal action of some viruses, including the human immunodeficiency virus (HIV), herpes simplex virus, hepatitis C virus and cytomegalovirus, among others, several reviews have appeared concerning their synthesis, therapeutic applications and mechanism of action. The majority of nucleoside analogues consist of modifications of natural substrates in the heterocyclic base or the sugar moiety. The general structure of a nucleoside analogue is well-defined by three key elements: i) the hydroxymethyl group, which is needed for activation through phosphorylation by kinases, ii) the heterocyclic base, which is needed for the recognition by the enzymes and the complementary strand in the nucleic acid synthesis process, and iii) the spacer, (the furanose ring in natural compounds) which present the two former groups in the adequate disposition. In this respect, it is interesting to speculate that the biological effects exhibited by nucleoside analogues depend importantly on the relative disposition of the hydroxy methyl group and the base moiety.

Figure 1. General structure of a nucleoside

Due to the high specifity of 5'-phosphorylating kinases only a few variations are allowed regarding the hydroxymethyl group. There are a vast family of compounds grouped under the name of nucleoside antibiotics that present complex side chains instead of the hydroxymethyl group. Hydrogen bond interactions of heterocyclic bases are fundamental for the biological activity of nucleoside analogues. So, any variation of the base moiety should preserve such intramolecular forces. As a consequence, only minor variations of bases are found in biologically active nucleoside analogues. The most notable of that sort of structural modifications is found in C-nucleosides, in which the typical C-N glycosidic bond has been replaced by a non-hydrolizable C-C bond.

On the other hand, numerous variations are possible for the spacer whilst still retaining activity. The relative 1',4' disposition of the hydroxymethyl group and the heterocyclic base can also be modified in order to obtain the so-called isonucleosides, compounds from both D- and L- enantiomeric series that have shown antiviral activities.

The structural modifications of the spacer backbone also led to active compounds. Replacement of the furanose ring by an acyclic chain, which can adopt a conformation similar to conventional nucleosides, gives rise to the acyclonucleosides, from which acyclovir, gancyclovir and their prodrugs are the best known. The furanose ring can also be replaced by a different carbo or heterocyclic ring. The carbocyclic analogues are also relevant compounds. Pyranosyl nucleoside analogues have also been proposed an alternative to conventional nucleosides in oligonucleotide chains. The corresponding analogues having a four-membered ring (oxetane) instead the conventional furanose ring have also been considered.

Figure 2. Antiviral drugs

The interest in nucleoside analogues in which the furanose ring is replaced by a different heterocyclic ring (heterocyclic nucleosides) has appeared much more recently. It is the aim of the group of Bioorganic Chemistry to study and develop the methodologies for the construction of those novel nucleoside analogues.

More complex nucleosides such as polyoxins and nikkomycins are also studied in our group.

In particular, the polyoxins are a group of peptidyl nucleoside antibiotics produced in the fermentation broth of Streptomyces cacaoi var asoensis and that have been isolated and characterized by Isono and co-workers about thirthy years ago. In total, about fifteen compounds having closely related structures have been identified and designated with alphabetical letters. Their structure showed the presence of a unique ribofuranosyl a -amino acid nucleoside that constitutes the common skeleton to all of the members of the family. The nucleoside portion that eventually bears different pyrimidine bases is connected through amidic bonds to an open chain polyalkoxy a -amino acid and to an azetidine-2-carboxylic acid. This tripeptide structure is illustrated by the first member of the family, polyoxin A. Some polyoxins however are simply dipeptides incorporating in their structure only two of the above amino acids. This is the case of polyoxin J that in fact by hydrolytic degradation leads to the polyalkoxy a -amino acid 5- O -carbamoyl-polyoxamic acid and the amino acid nucleoside thymine polyoxin C.

Figure 3. General structure of Polyoxins

The original interest for polyoxins and the closely related natural products nikkomycins and neopolyoxins as well as their synthetic analogues stemmed from their marked activity against phytopathogenic fungi whereas are non toxic to bacteria, plants, or animals. These biological effects apparently are due to the ability of polyoxins to inhibit the enzyme chitin synthase and therefore to prevent the biosynthesis of chitin, an essential component of the fungal cell wall structure. Hence, the polyoxin complex obtained by fermentative processes proved to be an excellent agricultural fungicide of wide use, particularly for the sheath blight disease of rice plant. More recently, considerable attention to all the above families of peptidyl nucleosides antibiotics, especially nikkomycins and neopolyoxins has been addressed as inhibitors of opportunistic fungal infections by Candida albicans in immuno-compromised hosts, such as AIDS victims and organ transplant patients.

Figure 4. Differences in the cell wall of Candida Albicans upon treatment with polyoxins

From natural sources it is only possible to isolate typical furanose-containing compounds whereas in order to improve the activity novel analogues are needed. Due to the differences found in the biological activities of polyoxins and nikkomycins when measured against the enzyme (chitin synthase) and Candida albicans in culture it is of high interest to prepare new analogues which could be more effective as anticandidal agents. In this regard the Bioorganic Chemistry group of ICMA has also been paid attention to the synthesis of structural analogues of polyoxins and nikkomycins.

Figure 4. Commercial sources of Polyoxins

In our laboratory is an ongoing program aimed at demonstrating the versatility of chiral nitrones

and hydroxylamines as building blocks for the efficient construction of biologically interesting nitrogenated compounds. In particular, we are interested in the synthesis of isoxazolidinyl nucleosides, the class of nucleoside analogues in which the furanose ring has been replaced by an isoxazolidine ring. Our experience in Organic Synthesis allows us to suggest that isoxazolidinyl nuleoside analogues of complex nucleosides can be synthesized by applying our nitrone-based methodology. Thus our goal is to design novel isoxazolidinyl analogues of both conventional nucleosides and complex nucleosides including nucleoside antibiotics such as polyoxins and nikkomycins.

Acknowledgements

We thank for their support the Ministry of Science and Technology (MCYT, Spain) and FEDER Program (Project CASANDRA, BQU2001-2428) and the Government of Aragon (Project P116-2001).

References

  • [1] P. Merino, S. Franco, F.L. Merchan, J. Revuelta, T. Tejero, Tetrahedron Lett. 2002, 43 , 459-452.
  • [2] P. Merino, J. Revuelta, T. Tejero, U. Chiacchio, A. Rescifina, A. Piperno, G. Romeo, Tetrahedron Asymmetry 2002 , 13 , 167-172
  • [3] P. Merino, A. Piperno, A. Rescifina, G. Romeo, R. Romeo, T. Tejero, Tetrahedron , 2003 , 5 9 , 4733.
  • [4] P. Merino, S. Franco, D. Lafuente, F.L. Merchan, J. Revuelta, T. Tejero Eur. J. Org. Chem . 2003 , 2877.
  • [5] P. Merino, T. Tejero, M. Laguna, E. Cerrada, A. Moreno, J. A. Lopez Org. Biomol. Chem. 2003 , 1 , 2336.
  • [6] P. Merino, S. Franco, F.L. Merchan, P. Romero, T. Tejero, S. Uriel Tetrahedron: Asymmetry 2003 , 14 , 3731.
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©2017 Instituto de Ciencia de Materiales de Aragón | Tfno: 976 761 231 - Fax: 976 762 453
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